This invention pertains to a sustained release formulation of calcium channel blockers microencapsulated by ethylcellulose and the process for preparing the formulation. Calcium channel blockers, such as diltiazem, nifedipine, and verapamil, modulate the transmembrane influx of calcium ions into both smooth and cardiac muscle. As the contractile processes of these muscles are dependent upon the movement of extracellular calcium ions into their cells, use of calcium channel blockers results in potent cardio-vascular effects. These results include decreased vascular resistance, slowed atrioventricular (A-V) conduction, reduced contractile tension, and reduced oxygen requirement of the heart muscle. Furthermore, the reduced calcium influx produced by calcium channel blockers interferes with excitation-contraction coupling of vascular smooth muscle, offering the therapeutic advantage of concomitant coronary and systemic vasodilation similar to the effect exerted by nitrates. Calcium channel blockers have been shown to be useful in alleviating symptoms of chronic heart disease, particularly cardiac arrythmias and essential hypertension.
Calcium channel blockers are conventionally administered in tablet or capsule form. Recently, a patent for a sustained release tablet formulation of diltiazem has issued in which release rate is controlled by the application of a diffusion controlled membrane to a matrix tablet containing swellable hydrophilic polymers (U.S. Pat. No. 5,000,962, Sangekar, et al.).
Other formulations of calcium channel blockers have also been patented. Ecanow suggests incorporation of veramapil hydrochloride into a coacervate-based, matrix-enveloped composition (U.S. Pat. No. 4,963,367). Microcapsules of diltiazem are also suggested for injectable preparations. Okada, et al. prepare these microcapsules in a water-in-oil emulsion (U.S. Pat. No. 4,917,893 and Yamamoto, et al. prepare these microcapsules in a water-in-oil-in-water emulsion (U.S. Pat. No. 4,954,298). More recently, Debregeas, et al. disclose a slow release Galenical preparation of diltiazem (U.S. Pat. No. 4,960,596).
Gergely, et al. disclose instant granules which contain a granulated carbohydrate carrier material, and a coating which is insoluble in water containing the pharmaceutically active ingredient (U.S. Pat. No. 4,888,177). Kitanishi, et al. disclose slow releasing granules characterized by coating quick-releasing granules which contain the active ingredient, polyvinylpyrrolidone, and a disintegrator (U.S. Pat. No. 4,971,805). Fulberth, et al. disclose a delayed action drug prepared by coating nonpareils with an adhesive solution, applying the drug, and coating with lacquer (U.S. Pat. No. 3,835,221).
Panoz, et al. disclose a controlled absorption diltiazem pellet with a core of diltiazem in association with an organic acid and a lubricant and a multi-layer outer membrane containing layers of water insoluble and water soluble synthetic polymers. The number of layers and the ratio of polymers are defined so as to result in a specified rate of dissolution (U.S. Pat. No. 4,721,619). Geoghegan, et al. disclose improvements to this general formulation in which the specified rate of dissolution differs from the previous invention (U.S. Pat. Nos. 4,891,230 an 4,917,899).
Microencapsulation technology ha long been used for the controlled delivery of pharmaceuticals. As early as 1964 aspirin was encapsulated in ethylcellulose (Miller, et al., U.S. Pat. No. 3,155,590) with improvements made to the basic process by Anderson, et al. (U.S. Pat. No. 3,341,416). Microencapsulation has also been used to deliver potassium salts to humans (Lippmann, et al., U.S. Pat. No. 4,259,315).
Other drugs have also been microencapsulated using variety of methods. For example, Newton, et al. disclose microcapsules with a higher than usual density by including a weighting agent, such as barium sulphate, to increase the residence time in the stomach (U.S. Pat. No. 4,938,967). Roswell, et al. disclose a controlled release formulation which contains additional particles of the active substance adhered to the surface of the coating (U.S. Pat. No. 4,574,080). Frank, et al. disclose a process for encapsulation by dissolving the compound to be encapsulated in a solvent, mixing the solution with a solution of encapsulating material and electrolyte, and gelling the encapsulating material (U.S. Pat. No. 4,606,940).
Microencapsulation technology has also been used for the controlled delivery of calcium channel blockers. The following are some examples.
Samejima, et al. disclose various microcapsules and processes of producing the same. Microcapsules of ethylcellulose are disclosed by flocculation in the presence of an organosilicon polymer and optionally a surfactant (U.S. Pat. No. 4,411,933); by incorporation of a polymer material which shows at least a 1.2 times increase in weight by immersion in water at 37 degrees C. (U.S. Pat. No. 4,462,982); and by use of a phase-separation-inducing agent soluble in cyclohexane, having a molecular weight of 150-3,000 and a solubility parameter of 7-10 cal/cm (U.S. Pat. No. 4,542,042).
Samejima, et al. also disclose free-flowing microcapsules of various coating materials by effecting the phase separation-flocculation of the coating polymer in the presence of ethylcellulose to minimize the coagulation of the coating polymer (U.S. Pat. No. 4,443,497) and a controlled release dosage which contains an inner core of medicament, an inner coating of ethylcellulose and a hydrophobic substance, and an outer coating of medicament (U.S. Pat. No. 4,963,365).
One of the primary reasons for encapsulating a drug is to slow the release of the drug into the body. Thus, a controlled release microencapsulated formula may be substituted for several non-microencapsulated doses. The release rate of the drug is typically controlled primarily through the thickness of the coating. Typically the release pattern is first order in which the rate decreases exponentially with time until the drug is exhausted (Kirk-Othmer, Encyclopedia of Chemical Technology, p.485, 1981). This release pattern is due to the fact that the concentration difference between that inside and that outside the capsule decreases continuously during dissolution.
However, often a zero order, constant- release rate is preferred in which case the microcapsules deliver a fixed amount of drug per unit time over the period of their effectiveness. This invention uses a novel combination of parameters to provide a controlled release, approximately zero order microencapsulated formulation of calcium channel blockers.